Many diabetics suffer from a severe cardiomyopathy even in the absence of vascular disease. This diabetic cardiomyopathy may predispose diabetics to heart failure and mortality from myocardial infarction. Evidence from animal models suggests that oxygen free radicals play an important role in the development of diabetic cardiomyopathy. Our laboratory has developed transgenic mouse models that are protected from cardiac free radical damage by targeted overexpression of the scavengers, catalase and metallothionein (MT) in the heart. We are also developing a transgenic model that overexpresses the scavenger manganese super oxide dismutase in the heart. This proposal will utilize these transgenic mice to test the hypotheses that free radical damage contributes to diabetic cardiomyopathy and that increased expression of free radical scavengers will protect the heart from diabetic cardiomyopathy. Transgenic mice protected from cardiac free radicals will be crossed to a transgenic model of severe, prolonged and early onset diabetes that we have found to display morphological features of diabetic cardiomyopathy. Diabetic mice carrying the free radical protective transgenes will be compared to unprotected diabetic mice for signs of cardiomyopathy. Hearts will be analyzed for differences in morphology, contractility, sensitivity to ischemia and indices of free radical damage. These results will provide strong evidence on the role of free radicals in diabetic cardiomyopathy and they will demonstrate the potential of antioxidant therapy. Our initial results indicate that overexpression of MT provides dramatic protection from the morphological damage of diabetic cardiomyopathy.